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Identification of molecular mechanisms and the targets using in vitro carcinogenesis model of endometrial cancer.

使用子宫内膜癌体外致癌模型鉴定分子机制和靶点。

基本信息

批准号：
20390432
负责人：
KYO Satoru
金额：
$ 12.31万
依托单位：
Kanazawa University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2008
资助国家：
日本
起止时间：
2008 至 2010
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-20390432/
关键词：
子宮内膜癌癌化モデル分子標的

项目摘要

In the present study, we investigated the molecular targets of KRAS signals using tumorigenic cells with oncogenic KRAS mutation established from TERT-immortalized endometrial epithelial cells. We first confirmed that the Raf-Erk pathway, but not the PI3K-Akt pathway, was activated in KRAS-tumorigenic cells. However, the introduction of constitutively active MEK into immortalized cells to mimic Raf-Erk activation failed to obtain tumorigenic phenotypes, indicating the existence of other carcinogenic pathways triggered by KRAS Recent evidence suggestive of linkage with KRAS signals prompted us to examine the involvement of NF-κB in endometrial carcinogenesis. We found that the DNA binding activity of NF-κB was markedly elevated in KRAS-tumorigenic cells compared to TERT-immortalized cells. Furthermore, the ability of NF-κB to activate the target gene promoters significantly increased in KRAS-tumorigenic cells. Introduction of a mutant IκB that is resistant to degradation and thereby enhances the inhibitory effect on NF-κB largely abrogated the transformed phenotypes of KRAS-tumorigenic cells. Thus, oncogenic KRAS signals contributed to the tumorigenic phenotypes of endometrial cells by activating the transcription function of NF-κB. These findings clearly show that NF-κB activation is a novel target of oncogenic KRAS in endometrial carcinogenesis, implying the potential utility of NF-κB inhibitors for endometrial cancer chemoprevention, especially with KRAS mutation.

在本研究中，我们利用从TERT永生化的子宫内膜上皮细胞中建立的具有致癌基因KRAS突变的肿瘤细胞来研究KRAS信号的分子靶点。我们首次证实Raf-Erk通路，而不是PI3K-Akt通路，在KRAS致瘤细胞中被激活。然而，在永生化细胞中引入结构性活性的MEK来模拟RAF-ERK的激活未能获得致癌表型，这表明存在KRAS触发的其他致癌途径。最近有证据表明与KRAS信号相关联，促使我们研究了NF-κB在子宫内膜癌发生中的作用。我们发现，与永生化细胞相比，KRAS致瘤细胞中的NF-κB的DNA结合活性显著升高。此外，在KRAS致瘤细胞中，NF-κB激活靶基因启动子的能力显著增强。一个耐降解的突变体IκB的引入，从而增强了对NF-κB的抑制作用，在很大程度上取消了KRAS致瘤细胞的转化表型。因此，致癌的KRAS信号通过激活NF-κB的转录功能参与了子宫内膜细胞的致癌表型。这些发现清楚地表明，NF-κB的激活是致癌KRAS在子宫内膜癌发生中的一个新的靶点，暗示了NF-κB抑制剂在子宫内膜癌化学预防中的潜在应用，特别是在KRAS突变的情况下。